Acute myeloid leukaemia (AML) is a genetically heterogeneous malignancy associated with poor prognosis and limited treatment options. To identify molecular programs conserved across AML subtypes and p Show more
Acute myeloid leukaemia (AML) is a genetically heterogeneous malignancy associated with poor prognosis and limited treatment options. To identify molecular programs conserved across AML subtypes and perturbations, we analysed three RNA sequencing datasets that captured venetoclax treatment under metabolic stress and the knockdown of chromatin regulators (PSPC1, JMJD1C, and RUNX1). Differential expression analysis was performed using DESeq2, followed by functional enrichment and network analyses. An independent AML cell line dataset was used to validate results. We identified a conserved 73-gene transcriptional signature that is consistently dysregulated across perturbations, characterised by the overexpression of CDKN1A, PHGDH, and ALDH1L2, and the downregulation of MYC and E2F targets. Functional analyses implicated cell cycle arrest, metabolic reprogramming, oxidative stress responses, and suppression of proliferative and biosynthetic pathways. PSPC1 emerged as a central hub linking chromatin remodelling to metabolic adaptation. Translational validation in the TCGA-LAML cohort revealed that higher 73-gene enrichment scores were associated with inferior overall survival, and stratification by hub gene expression recapitulated adverse prognostic trends. Collectively, these findings define a stress-adaptive transcriptional program conserved across diverse AML perturbations, providing mechanistic insights into the coupling of metabolism and the cell cycle, and potential therapeutic vulnerabilities. Incorporation of this 73-gene program into patient stratification frameworks may guide biomarker-driven therapies and combination strategies targeting metabolic and apoptotic stress responses. Show less